The present invention relates to a medicine, and more particularly relates to a medicine having a high affinity for MDR.
Benzodiazepine (Bz) receptors are recently classified into 2 subtypes of central benzodiazepine receptor (CBR) located on GABAA receptor/ion channel complex and mitochondrial DBI (diazepam binding inhibitor, Neuropharmacol., 30, 1425-1433 (1991)) receptor (BDR) located on the central nervous system (glial cells) or adrenal glands (Clin. Neuropharmacol., 16, 401-417 (1993)).
MDR agonists act indirectly on GABAA/ion channel complex via endogenous neurosteroids and cause an anti-anxiety action. Accordingly, they have a possibility to be usable for diseases (obsessive disorders, panic disorders) on which the previous Bzs do not have a satisfactorily therapeutic effect, and to alleviate side-effects such as excessive sedation or psychic dependence caused by the Bzs. Furthermore, MDR ligands act indirectly on GABAA receptors, and therefore, have a possibility of use as therapeutical agents of sleeping disorders, epilepsy, dyskinesia accompanied by muscle rigidity, feeding disorders, circulation disorders, recognition and learning disability or drug dependence (Progress in Neurobiology, 38, 379-395, 1992, ibid., 49, 73-97, 1996; J. Neurochem., 58, 1589-1601; Neuropharmacol., 30, 1435-1440, 1991). In addition, MDR ligands have a possibility of use as therapeutic agents of cancer (Biochimica et Biophysica Acta, 1241, 453-470, 1995), lipid metabolism abnormality (Eur. J. Pharmacol., 294, 601-607, 1995), schizophrenia (Neuropharmacology, 35, 1075-1079, 1996), cerebral infarction (J. Neurosci., 15, 5263-5274, 1995), AIDS (Abstracts of the fifth international conference on AIDS, p. 458, 1989), Alzheimer""s disease (Alzheimer Dis. Assoc. Disotd., 2, 331-336, 1988) or Huntington chorea (Brain Res., 248, 396-401, 1982).
Some phenoxyaniline derivatives are reported in WO9533715, JP 61040249 and JP 57208295. However, they have a hydrogen atom or an alkyl group as the substituent on the nitrogen atom of the aniline, but there are not reported the derivatives having a carbonyl group as the substituent. Furthermore, the use of the derivatives of the above-mentioned patent is anti-inflammatory agents based on the action to arakidonic acid series, anti-arteriosclerosis drugs based on an increase of PGI2 production, or heat sensitive recording materials, but there is not described affinity for MDR and anti-anxiety based on affinity for MDR.
An object of the present invention is to provide pharmaceutical compounds which are effective on diseases on which the previous Bzs do not have a satisfactorily therapeutic effect, and have a high affinity for MDR, and therefore, have a therapeutic or preventive effect on the central diseases such as anxiety, related diseases thereto, depression, epilepsy, etc. without side-effects such as excessive sedation or psychic dependence caused by the Bzs. Furthermore, another object of the present invention is to provide therapeutic agents of sleeping disorders, dyskinesia accompanied by muscle rigidity, feeding disorders, circulation disorders, recognition and learning disability, drug dependence, cancer, lipid metabolism abnormality, schizophrenia, cerebral infarction, AIDS, Alzheimer""s disease or Huntington chorea.
As a result of extensive researches about aryloxyaniline derivatives, the present inventors have found novel aryloxyaniline derivatives having a high affinity for MDR, thus the present invention has been accomplished.
The present invention is illustrated as follows: the present invention is directed to an aryloxyaniline derivative represented by Formula [I]: 
wherein Ar1 and Ar2 are the same or different, and are each a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group or naphthyl group, R1 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted phenyl group or a group of the formula: xe2x80x94NR2(R3) (wherein R2 and R3 are the same or different, and are each a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or R2 and R3 taken together with the nitrogen atom to which they are attached form a 4 to 10 membered cyclic amino group), X1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, a trifluoro-methyl group, a carbamoyl group or an aminosulfonyl group, y1 is a branched or unbranched alkylene group having 1 to 6 carbon atoms or a single bond; or a pharmaceutically acceptable salt thereof.
In the present invention, the substituted phenyl group is a phenyl group substituted with one to three members selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, an alkyl group having 1 to 10 carbon atoms substituted with halogen atoms; hydroxyl groups; alkanoyloxy groups having 1 to 10 carbon atoms; carboxyl groups or alkoxycarbonyl groups, an alkenyl group having 2 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, a group of the formula: xe2x80x94Oxe2x80x94Zxe2x80x94R4 (wherein Z is a branched or unbranched alkylene group having 1 to 10 carbon atoms, and R4 is an amino group, an amino group substituted with one or two of an alkyl group having 1 to 7 carbon atoms, a cyclic amino group having 2 to 7 carbon atoms, a hydroxyl group, a carboxyl group or an alkoxycarbonyl group), an alkanoyl group having 2 to 10 carbon atoms or a ketal form thereof, a formyl group or an acetal form thereof, a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, a carbamoyl group, a carbamoyl group substituted with one or two of an alkyl group having 1 to 10 carbon atoms on the nitrogen atom, an aminosulfonyl group, an aminosulfonyl group substituted with one or two of an alkyl group having 1 to 10 carbon atoms on the nitrogen atom, a halogen atom and a nitro group, and examples thereof are a 2-methylphenyl group, a 2-propylphenyl group, a 2-isopropylphenyl group, a 2-cyclopentylphenyl group, a 2-(1-hydroxyethyl)phenyl group, a 2-carboxymethylphenyl group, a 2-methoxycarbonyl-phenyl group, a 2-vinylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-ethoxyphenyl group, a 2-hexyloxyphenyl group, a 2-isopropoxyphenyl group, a 2-cyclopentoxyphenyl group, a 2,5-dimethoxyphenyl group, a 2,4,6-trimethoxyphenyl group, a 4-methylthiophenyl group, a 2-isopropylthiophenyl group, a 4-cyclohexylthiophenyl group, a 2-(2-dimethylamino-ethoxy)phenyl group, a 2-(2-hydroxyethoxy)phenyl group, a 2-carboxymethoxyphenyl group, a 2-methoxycarbonylmethoxyphenyl group, a 2-acetylphenyl group, a 2-(2-methyl-1,3-dioxolan-2-yl)phenyl group, a 2-formylphenyl group, a 2-(1,3-dioxolan-2-yl)phenyl group, a 2-carboxylphenyl group, a 2-(N-methylaminocarbonyl)phenyl group, a 2-(N,N-dimethylamino-carbonyl)phenyl group, a 2-aminocarbonylphenyl group, a 2-aminosulfonylphenyl group, a 4-aminosulfonylphenyl group, a 2-methylaminosulfonylphenyl group, a 2-dimethylamino-sulfonylphenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2,4-difluorophenyl group, a 2-nitrophenyl group, a 2-aminophenyl group, a 2-pyrrolidinophenyl group and a 4-dimethylaminophenyl group. The substituted pyridyl group refers to a pyridyl group substituted with a straight or branched alkoxy group having 1 to 10 carbon atoms, and examples thereof are a 2-methoxy-3-pyridyl group, a 3-methoxy-2-pyridyl group and a 4-methoxy-3-pyridyl group. The alkyl group having 1 to 10 carbon atoms refers to a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a cyclobutyl group, a cyclopropylmethyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a cyclobutylmethyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a cyclohexyl group, a cyclopentylmethyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, a cyclohexylmethyl group, an octyl group, a nonyl group and a decyl group. The substituted alkyl group having 1 to 10 carbon atoms refers to an alkyl group substituted with a hydroxyl group, an alkanoyloxy group, an alkanoyl group, an alkoxy group, a halogen atom, an azido group, an amino group or a carboxyl group, and examples thereof are a hydroxymethyl group, an acetyloxymethyl group, a methoxymethyl group, a chloromethyl group, a trifluoromethyl group, an azidomethyl group, an aminomethyl group, a dimethylaminomethyl group and a pyrrolidinomethyl group. The alkoxy group having 1 to 10 carbon atoms refers to a straight, branched or cyclic alkoxy group, and examples thereof are a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a cyclopropylmethoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy group and a decyloxy group. The alkyl group having 1 to 10 carbon atoms represented by R2 and R3 refers to a straight, branched or cyclic alkyl group, accordingly, when R2 and R3 are each the alkyl group having 1 to 10 carbon atoms, examples of the group of xe2x80x94NR2(R3) are a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a cyclopropyl-methylamino group, a pentylamino group, an isopentylamino group, a cyclopentylamino group, a cyclobutylmethylamino group, a 1-ethylpropylamino group, a hexylamino group, an isohexylamino group, a cyclohexylamino group, a cyclopentyl-methylamino group, a 1-ethylbutylamino group, a heptylamino group, an isoheptylamino group, a cyclohexylmethylamino group, an octylamino group, a nonylamino group, a decylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutylamino group, a dipentylamino group, a dihexylamino group, an N-methylethylamino group, an N-methylpropylamino group, an N-methylbutylamino group, an N-methylpentylamino group, an N-methylhexylamino group, an N-ethylpropylamino group, an N-ethylbutylamino group and an N-ethylpentylamino group. The 4 to 10 membered cyclic amino group represented by the group of xe2x80x94NR2(R3) refers to a cyclic amino group which may optionally have a nitrogen atom or an oxygen atom, and examples thereof are a pyrrolidino group, a piperidino group, a piperazino group, an N-methylpiperazino group and a morpholino group. The alkyl group having 1 to 5 carbon atoms represented by X1 refers to a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a cyclobutyl group and a cyclopropylmethyl group. The alkoxy group having 1 to 5 carbon atoms refers to a straight, branched or cyclic alkoxy group, and examples thereof are a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and a cyclopropylmethoxy group. Examples of the branched or unbranched alkylene group having 1 to 6 carbon atoms represented by Y1 are a methylene group, an ethylene group, a propylene group, a methylmethylene group and a dimethylmethylene group. The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples of the pharmaceutically acceptable salt in the present invention are salts with mineral acids (e.g. sulfuric acid, hydrochloric acid or phosphoric acid), organic acids (e.g. acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid or benzenesulfonic acid), metal ions (e.g. a sodium ion, a potassium ion or a calcium ion), organic bases (e.g. diethanolamine) or ammonium salt.
The compound of Formula [I] can be prepared by the following general preparation methods 1 to 6. In the following reaction formulae, Ar1, Ar2, R1, X1 and Y1 are as defined above, y2 is a single bond or an alkylene group having 1 to 5 carbon atoms which is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms, R5 is an alkyl group having 1 to 3 carbon atoms or a hydrogen atom, X2 is an acyloxy group having 1 to 10 carbon atoms, a chlorine atom, a bromine atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, X3 is a chlorine atom, a bromine atom or an iodine atom.

An aniline derivative (1) is reacted with a carbonyl derivative (2) in the presence or absence of an acid catalyst in an inert solvent and subjected to reduction, or a mixture of the aniline derivative (1) and the carbonyl derivative (2) is subjected to reduction in the presence or absence of an acid catalyst in an inert solvent to give a compound (3). The compound (3) is reacted with an N-carbonylating agent in the presence or absence of a base in an inert solvent to give a compound (4) of the present invention. Alternatively, phosgene as the N-carbonylating agent is reacted with the compound (3) to give a chlorocarbonyl derivative, which is then reacted with an alcohol or an amine in the presence or absence of a base, thereby the compound (4) of the present invention is also obtained.
Examples of the acid catalyst are a halogenated hydrogen (e.g. hydrogen chloride or hydrogen bromide), an inorganic acid (e.g. hydrochloric acid or sulfuric acid), an organic acid (e.g. acetic acid or tosylic acid), PPTS, piperidine hydrochloride, etc.
The reduction is carried out by using a borane reductant (e.g. sodium borohydride, lithium borohydride or sodium cyanoborohydride), or an aluminum reductant (e.g. lithium-aluminum hydride), or carried out by hydrogenation using a catalyst such as palladium, platinum dioxide or Raney nickel. Examples of the N-carbonylating agent are an acyl halide, an organic acid anhydride, an alkoxycarbonyl halide, a carbamoyl halide, cyanic acid (formed from potassium cyanate and acetic acid in the reaction solution) and an isocyanate. Examples of the base are an organic amine (e.g. triethylamine, diisopropylethylamine or pyridine), and an inorganic base (e.g. potassium carbonate, sodium hydroxide, sodium hydride or a metallic sodium). Examples of the inert solvent are an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran), a hydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbon solvent (e.g. chloroform or dichloromethane), acetonitrile, water and a mixture thereof.

A compound (7), i.e. the compound (3) wherein R5 is a hydrogen atom, is also obtained by reacting the aniline derivative (1) with a carboxylic anhydride, an acyl halide, a carboxylic acid or a carboxylic acid ester, each of which is represented by a compound (5), in the presence or absence of a base in an inert solvent to give an amide compound (6), and then reacting the amide compound (6) with a reductant in an inert solvent.

The aniline derivative (1) is reacted with an N-carbonylating agent in the presence or absence of a base in an inert solvent to give a compound (8), which is then reacted with a halogenated compound (9) in the presence of a base, if necessary, by using a phase transfer catalyst, a copper powder or a cuprous halide in an inert solvent, thereby there is obtained a compound (10) of the present invention. Alternatively, phosgene as the N-carbonylating agent is reacted with the compound (1) to give a chlorocarbonyl derivative, which is then reacted with an alcohol or an amine in the presence of a base, thereby there is also obtained the compound (8).
Examples of the N-carbonylating agent are an acyl halide, an organic acid anhydride, an alkoxycarbonyl halide, a carbamoyl halide, cyanic acid (formed from potassium cyanate and acetic acid in the reaction solution) and an isocyanate. Examples of the base are an organic amine (e.g. triethylamine, diisopropylethylamine or pyridine), an inorganic base (e.g. potassium carbonate, sodium hydroxide, sodium hydride or metallic sodium) and an alcoholate (e.g. potassium t-butoxide or sodium ethoxide). Examples of the phase transfer catalyst are a quaternary ammonium salt (e.g. benzyltriethyl ammonium bromide) or a crown ether (e.g. 18-crown-6 ether). Examples of the inert solvent are an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran), a hydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbon solvent (e.g. dichloromethane or chloroform), a ketone solvent (e.g. acetone), acetonitrile, N,N-dimethylformamide, nitrobenzene, water and a mixture thereof.
When one or both of Ar1 and Ar2 have nitro groups, the nitro groups can be each converted into an amino group by a hydrogenation or a metal reduction. The amino group is reacted with a halogenated compound in the presence of a base, if necessary, by using a phase transfer catalyst in an inert solvent to be converted into an amino group substituted with a straight, branched or cyclic alkyl group having 1 to 10 carbon atoms.
The hydrogenation is carried out by using a catalyst such as palladium, platinum dioxide or Raney nickel, and the metal reduction is carried out by using a metal or a metal salt such as tin, a stannous salt (e.g. stannous chloride), iron, a ferrous salt (e.g. ferrous chloride) or zinc under conventional acidic, basic or neutral conditions. Examples of the base are an organic amine (e.g. triethylamine, diisopropylethylamine or pyridine), an inorganic base (e.g. potassium carbonate, sodium hydroxide, sodium hydride or metallic sodium), and an alcoholate (e.g. potassium t-butoxide or sodium ethoxide). Examples of the phase transfer catalyst are a quaternary ammonium salt (e.g. benzyltriethyl ammonium bromide) and a crown ether (e.g. 18-crown-6 ether). Examples of the inert solvent are an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran), a hydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbon solvent (e.g. dichloromethane or chloroform), acetonitrile, N,N-dimethylformamide, water and a mixture thereof.
When one or both of Ar1 and Ar2 have acyloxy groups, the acyloxy groups can be each converted into a hydroxyl group by hydrolysis under acidic or basic conditions. The hydroxyl group is reacted with a halogenated compound in the presence of a base, if necessary, by using a phase transfer catalyst in an inert solvent to be converted into a straight or branched alkoxy group having 1 to 10 carbon atoms, a straight or branched alkoxy group having 1 to 10 carbon atoms which is substituted with a substituted or unsubstituted amino group, or an alkoxy group having 1 to 10 carbon atoms which is substituted with a carboxyl group or an alkoxycarbonyl group.
The acidic or basic conditions mean to use an inorganic acid (e.g. hydrochloric acid or sulfuric acid) or an inorganic base (e.g. sodium hydroxide or potassium hydroxide) in a solvent such as an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran or dioxane), a ketone (e.g. acetone), acetonitrile, N,N-dimethylformamide, water or a mixture thereof. Examples of the base are an organic amine (e.g. triethylamine, diisopropylethylamine or pyridine), an inorganic base (e.g. potassium carbonate, sodium hydroxide, sodium hydride or metallic sodium), and an alcoholate (e.g. potassium t-butoxide or sodium ethoxide). Examples of the phase transfer catalyst are a quaternary ammonium salt (e.g. benzyltriethyl ammonium bromide) and a crown ether (e.g. 18-crown-6 ether). Examples of the inert solvent are an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran), a hydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbon solvent (e.g. dichloromethane or chloroform), acetonitrile, N,N-dimethylformamide, water and a mixture thereof.
When one or both of Ar1 and Ar2 have alkoxycarbonyl groups, the alkoxycarbonyl groups are each converted under conventional hydrolysis conditions of an ester into a carboxyl group, which can be then converted into an alkoxy-carbonyl group having 1 to 10 carbon atoms by esterification, or into a primary or secondary alkylaminocarbonyl group having 1 to 10 carbon atoms or an aminocarbonyl group by amidation.
The hydrolysis conditions mean a reaction of a base (e.g. sodium hydroxide or potassium hydroxide or sodium carbonate) or an inorganic acid (e.g. hydrochloric acid or sulfuric acid) in an inert solvent such as an alcohol (e.g. methanol or ethanol) or a ketone (e.g. acetone). The esterification means a reaction of an alkyl compound which is substituted with chlorine atoms, bromine atoms or iodine atoms, or a dialkyl sulfate, together with an inorganic base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydride), an alcoholate (e.g. sodium methoxide or potassium t-butoxide) or an organic base (e.g. triethylamine or diisopropylethyl-amine), or a reaction of an alcohol with an acid (e.g. hydrogen chloride or sulfuric acid). The amidation is carried out by converting the carboxyl group with thionyl chloride or triphenylphosphine-carbon tetrachloride into an acid halide, and then by reacting the acid halide with a corresponding amine derivative, or carried out by a conventional amidation (e.g. a mixed acid anhydride method or a dicyclohexylcarbodiimide method).
When one or both of Ar1 and Ar2 have formyl or acyl groups, carbonyl groups of the formyl or acyl groups are each reacted with a Wittig reagent to be converted into an alkenyl group, which is then converted into an alkyl group by reduction.
The Wittig reagent includes a triphenylalkyl-phosphonium halide having an alkyl group having 1 to 9 carbon atoms or a diethylalkyl phosphonate, and it is used in an inert solvent such as an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran), a hydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbon (e.g. methylene chloride or chloroform), acetonitrile or N,N-dimethylformamide together with a base such as sodium hydride, potassium t-butoxide, sodium ethoxide or n-butyl lithium, if necessary, further together with a phase transfer catalyst such as a quaternary ammonium salt (e.g. benzyltriethyl ammonium bromide) or a crown ether (e.g. 18-crown-6 ether). The reduction includes hydrogenation which is carried out by using a catalyst such as palladium, platinum dioxide or Raney nickel.
When one or both of Ar1 and Ar2 have formyl or acyl groups, carbonyl groups of the formyl or acyl groups are each reacted with a Grignard reagent to be converted into a sec- or tert-alcohol compound. The sec-alcohol compound is oxidized with various oxidants to be converted into an acyl group.
The Grignard reagent includes an alkyl or alkenyl magnesium halide having 1 to 9 carbon atoms such as methyl magnesium bromide or ethyl magnesium bromide. The oxidant includes oxalyl chloride-dimethyl sulfoxide (Swern Oxidation), a chromic oxidant, a metal oxidant such as manganese dioxide.
For the use of the compounds of the present invention as medicines, the compounds of the present invention are mixed with conventional additives such as a filler, a binder, a disintegrater, a pH regulator or a solubulizer to form tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions or injections, all of which can be prepared by conventional techniques.
The compound of the present invention can be administered orally or parenterally in the amount of from 0.1 to 500 mg/day to an adult patient in a single dose or several divided doses. This dose can be varied depending on the type of diseases, age, body weight or symptoms of each patient.